The first purpose of these investigations is to define some of the cellular and molecular aspects of T- and B-cell differentiation through comparative studies in mice, rabbits, chickens, frogs and humans. Integrated studies of individuals with leukemias, lymphomas and immunodeficiencies will be the other major focus. Using immunofluorescent and biochemical techniques, we will examine the nature of the immunoglobulin components expressed by pre-B cells from normal tissues, cell lines and pre-B hybridomas, with emphasis on the genetic diversity of variable regions of IgM heavy chains. Anti-idiotype antibodies and isoelectric focusing will be used to examine normal generation of clonal diversity, the cellular basis of pauci-clonal antibody responses and the extent of clonal involvement of murine plasmacytomas and a spectrum of B-cell malignancies in humans, adoptive transfer and/or in vitro model systems will also be used to examine these issues. Generation of isotype diversity will be examined in frogs (IgM and IgG), chickens (IgD) and man (IgA1 and IgA2). The immunosuppressive effects of anti-Ia will be investigated along with phylogenetic aspects of Ia structure and function. We will continue to examine human T-cell subpopulations, especially TM and TG cells, and search for VH expression by human T cells. Antibodies to clathrin will be used to study the role of this highly conserved protein in lymphocyte activation and differentiation. Hybridoma antibodies will play a central role in these studies, and somatic cell hybridization used to examine generation of VH and isotype diversity and to map genes for human immunoglobulins.